ABSTRACT Supplement Title: Determination of Extracellular Vesicle Characteristics in Preclinical AD The overall objective of the ?Kansas Institute for Precision Medicine? (KIPM) COBRE at the University of Kansas Medical Center (KUMC) is to advance the customization of healthcare through promoting innovative scientific discoveries. Alzheimer's disease (AD) and related dementias (ADRDs) are being diagnosed at epidemic rates, with incidence to triple from 35 to 115 million cases worldwide. Most ADRDs are characterized by progressive neurodegeneration, and Alzheimer's disease is currently the sixth leading cause of death in the United States. This project, entitled ?Determination of extracellular vesicle characteristics in preclinical AD,? is a supplement to the KIPM COBRE. There is evidence that aerobic exercise provides brain benefits in Alzheimer's Disease patients, by improving cognitive performance and slowing structural decline in aging, but the mechanisms of this benefit are unclear. A potential and understudied mechanism of benefit involves extracellular vesicles (EV's). EV's are lipid bilayer particles that can be released from tissues, such as muscle, in response to exercise and can travel to the brain. EV's can carry protein components, such as heat shock proteins, which are produced by cells in response to stress and play key roles in proteostasis. HSP's actively modulate processes such as aggregation, transport, folding of other proteins and may limit damage to the cell. This is likely particularly important in diseases, such as AD, which are marked by pathological protein aggregation. However, no studies have characterized the relationship between EV's and AD brain neuropathology, or the response of EV's to an exercise intervention in individuals at risk for AD. This precision medicine study will leverage unique resources available through the KIPM COBRE to characterize exosomes in existing blood samples from a clinical trial of individuals with preclinical AD that has recently been completed. It will also allow us to investigate the relationship between the EV response and cerebral amyloid burden, which has not been explored. We will also leverage a rich dataset of available neuroimaging data beyond just amyloid PET, probing the relationships between EV's, HSP's, and brain structure. Characterization of this important potential mechanism will provide insight on the brain benefits of exercise and also provide information on relationships with neuropathology during preclinical AD, a period of time before cognitive symptoms have appeared, when interventions are likely to have the greatest impact.